Human T-cell Leukemia Virus type 1 (HTLV-I) is the etiological agent of adult T-cell leukemia, an aggressive and fatal disease characterized by a clonal expansion of virus-infected CD4+T cells. It is estimated that 20 to 30 million people worldwide are infected with HTLV-I. Overall, survival of HTLV-I-infected patients with acute leukemia treated with various chemotherapy or radiotherapy regimens is limited and median survival is 8 months. Consequently, identification of new potential therapeutic targets is greatly needed. Our studies previously demonstrated that intracellular activated Notch1 (ICN1) is constitutively activated in HTLV-I-transformed T-cells and HTLV-I-associated adult T-cell leukemia, and is essential for tumor cell growth in an in vivo mouse model. Recent data from our laboratory suggest that the viral Tax oncoprotein reduces degradation of ICN1, leading to constitutive signaling in HTLV-I-infected cells. We further found that Tax- mediated NF-kappa B2 activation was involved in constitutive ICN1 signaling. Activation of the non-canonical NF-kB pathway has emerged as an important pathway involved in T-cell leukemia and lymphomas. The Nfkb2 gene is frequently involved in chromosomal translocations associated with human cutaneous T-cell lymphomas. In addition, activation of NF-kappaB is essential for HTLV-I-transformed cells and inhibition of the pathway prevents tumor growth in vitro and in vivo. This project will investigate the molecular mechanisms used by viral Tax to prevent the degradation of ICN1 and stimulate expression of its target genes. We will also examine the role of activated Notch in proliferation and inhibition of apoptosis in early phases of HTLV-I infection of T-cells.